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A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors
Oren J Becher1,2, Stephen W Gilheeney1, Yasmin Khakoo1,3
1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
Background:
The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination.
Procedure:
We performed a standard 3+3 phase I, open-label, dose-escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25-75 mg/m2 /day) and temsirolimus (25-75 mg/m2 IV weekly) were investigated.
Results:
Twenty-three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high-grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose-limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single-agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high-grade glioma; no partial or complete responses were achieved.
Conclusions:
The combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors.
Insights
This Phase I trial found that combining perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is safe for pediatric solid tumors. The combination therapy showed feasibility and manageable toxicities in young patients.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Molecular Targeted Therapy
Background:
- The PI3K/AKT/mTOR pathway is frequently activated in pediatric solid tumors like gliomas and medulloblastomas.
- Preclinical studies suggest that combining perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) effectively targets this pathway in pediatric gliomas.
- This study aimed to evaluate the safety, pharmacokinetics, and maximum tolerated dose of this combination therapy.
Purpose of the Study:
- To assess the safety and tolerability of combined perifosine and temsirolimus in pediatric patients with recurrent/refractory solid tumors.
- To determine the maximum tolerated dose (MTD) for this combination therapy.
- To evaluate the pharmacokinetic profile of perifosine and temsirolimus when administered together.
Main Methods:
- A standard 3+3 phase I, open-label, dose-escalation study was conducted.
- Patients with recurrent/refractory pediatric solid tumors were enrolled.
- Four dose levels of perifosine (25-75 mg/m²/day) and temsirolimus (25-75 mg/m² IV weekly) were investigated.
Main Results:
- Twenty-three pediatric patients with brain tumors, neuroblastoma, or rhabdomyosarcoma were treated.
- The combination was generally well-tolerated, with no dose-limiting toxicity observed.
- Common grade 3/4 toxicities included thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%).
- Pharmacokinetics for both agents were consistent with prior studies.
- Stable disease was observed in 9 of 11 patients with DIPG or high-grade glioma.
Conclusions:
- The combination of perifosine and temsirolimus is safe and feasible for treating pediatric patients with recurrent/refractory solid tumors.
- The regimen demonstrated manageable toxicity profiles.
- Further investigation into the efficacy of this combination in specific pediatric tumor types may be warranted.
